Robert O. Stafford

Glucocorticoid and Mineralocorticoid Activities of Δ1-Fluorohydrocortisonei

Summary (1) Comparisons have been made of relative potencies of hydrocortisone, fluorohydrocortisone, Δ1-hydrocortisone, and Δ1-fluorohydrocortisone in causing deposition of liver glycogen and reduction of sodium excretion in the adrenalectomized rat. (2) In glycogen deposition potency, the compounds have activity of the following magnitude: Δ1-fluorohydrocortisone acetate-50; fluorohy-drocortisone acetate-12.6; Δ1-hydrocorti-sone-2.9; hydrocortisone-1. (3) In sodium-retaining potency, the compounds have activity of the following magnitude: Δ1-fluorohydrocortisone acetate-4.6; fluorohydro-cortisone acetate-5.0; Δ1-hydrocortisone acetate-very slight; hydrocortisone acetate -very slight; DOCA-1.

Anti-Gonadal Hormone Activity of 1lα-Hydroxyproges terone

Summary 1. U-0384 (1lα-hydroxyprogesterone) partially counteracted the effects of exogenous estradiol in stimulating the uteri of ovariectomized rats and the seminal vesicles of castrated male rats. This compound also decreased the hypertrophy of the seminal vesicles, prostate, and levator ani muscle in castrated males injected with testosterone propionate. In intact rats U-0384 decreased the weight of the sex accessories by its anti-gonadal hormone activity and through its inhibitory effect on gonadotrophic hormone secretion. 2. This steroid has 110 estrogenic, androgenic, or progestational activity in the amounts assayed. This compound, when injected in large amounts,. produced only slight adrenal atrophy and no thymic involution, and can, therefore, be presumed to have very little or no adrenal cortical hormone activity. 3. Although the anti-estrogen and anti-androgen activity of this new steroid is limilted in animals, inasmuch as it lacks other gonadal hormone effects, it may be effective in therapy of some pathological conditions in which a reduction of endogenous sex hormones is considered desirable.

Effect of testosterone propionate on phosphatases in the seminal vesicle and prostate of the rat.

Summary The acid and alkaline phosphatases of seminal vesicles and prostate glands of rats were estimated quantitatively in normal animals, castrates, and castrates receiving testosterone propionate. In both glands the enzymes decrease in activity after castration, are restored to essentially normal levels by androgen therapy. The seminal vesicle is more sensitive than the prostate gland in this respect. Androgen therapy caused hypertrophy of the glands beyond normal, size, but under the conditions of these experiments, the acid and alkaline phosphatase active was not increased beyond normal levels.

Ability of some progestational steroids to stimulate male accessory glands of reproduction in the rat.

Summary When tested for ability to stimulate seminal vesicles and prostates of castrate, immature rats, a series of progestational steroids produced results as follows: 1) None of the compounds has androgenic activity approaching that of standard androgens, methyl-testosterone or testosterone propionate. 2) All compounds tested orally produced some stimulation of the prostate, although it was extremely slight in the case of 17α-acetoxy progesterone and 6α-methyl-17α-acetoxy progesterone. Significant stimulation of seminal vesicles was seen only with 17α-ethinyltestosterone, 17α-ethinyl-19-nortestosterone, and EN. 3) Of compounds tested subcutaneously, only 17α-(2-methallyl)-19-nortestosterone failed to stimulate the seminal vesicle. All compounds produced some stimulation of the prostate, although EN and 17α-(2-methallyl)-19-nortestosterone produced minimal responses.

Adrenal Corticoid Activities of 2-Methylhydrocortisone Acetate and 2-Methyl-9a-Fluorohydrocortisone Acetate

Summary (1) Two new analogues of hydrocortisone, 2-methylhydrocortisone acetate and 2-methyl-9 α-fluorohydrocortisone acetate, have been tested for corticoid activity on the following assays: anti-inflammatory, glycogen deposition, muscle work, and sodium retention. A summary of the data is presented in Table VI. (2) The sodium-retaining activity of 2-methyl-9 α-fluorohydrocortisone acetate is 90 x desoxycorticosterone acetate and is, therefore, one of the most potent mineralocorticoids.

Effects of 2-methylation on glucocorticoid activity of various C-21 steroids.

Summary The anti-inflammatory and glycogen deposition activities of some C-21 steroids and their 2-methyl analogues have been described. The 2-methyl analogues were more potent than the parent compound in the cases of hydrocortisone, 9α-fluorohydrocortisone, 6-dehydrohydrocortisone, 11β, 17α-dihydroxyprogesterone and 9α-fluoro-11β, 17α-dihydroxyprogesterone. In the cases of 11β-hydroxyprogesterone, corticosterone, 9α-fluorocorticosterone, 9α-fluoro-llβ-hydroxyprogesterone and 11-ketoprogesterone the 2-methyl did not potentiate the activity. The 2-methyl analogues of cortisone, 9α-fluorocortisone and 11-dehydrocorticosterone were less effective than the parent steroid.

Utility of 17α-Acetoxyprogesterone in Delaying Estrus in the Bitch

Summary When tested for ability to delay estrus in female dogs. 17α-acetoxyprogesterone successfully inhibited estrus during 70-wk treatment period. When incorporated in dog feed and fed ad lib., a minimum dose of 2.5 mg kg was effective. When administered once daily in suspension form a dose of 4 mg kg was required. Histopathological examination of ovaries of treated dogs revealed inhibition of development of vesicular follicles. Bitches previously treated with 17α-acetoxyprogesterone returned to cycle, were bred and whelped normal, healthy litters of puppies. It was suggested that bitches be bred no sooner than 6 mos after cessation of treatment to insure maximum fertility. Drug was judged completely safe for dogs. The author is indebted to members of Depts. of Pathology and Endocrinology. The advice of Drs. R. L. Johnston, R. A. Runnells, and R. O. Stafford. The Upjohn Co., and Dr. R. K. Meyer, Univ. of Wisconsin, is gratefully akcnowledged.

Fluorometholone, A Preferentially Anti-Inflammatory Gorticoid

Summary Fluorometholone is an unusual synthetic corticoid in the rat because its anti-inflammatory potency (131 X hydrocortisone) is much greater than its glucocorticoid potency (26 X hydrocortisone). Its potency in promoting development of ulcers of the pyloric portion of rat stomach is between its glucocorticoid potency and its anti-inflammatory potency. It does not cause sodium retention at doses in which a similar compound (differing only by presence of C-21 hydroxyl) does produce measurable sodium retention.

Comparison of Myotrophic and Androgenic Activities of 19-Nortestosterone Cyclopentylpropionate, Androstanolone, and Methylandrostenediol

Summary 1. Three steroids with protein anabolic activity were tested in parallel with testosterone propionate to compare their relative properties of stimulating the levator ani muscles and seminal vesicles of weanling castrate male rats when injected subcutaneously in oil solution or suspension. The androgenic and myotrophic potencies of the test compounds, as well as their myotrophic/andro-genic ratios, were calculated by analysis of significant portions of the data. 2. The androgenic potencies of these steroids, expressed as percentages of the potency of testosterone propionate, were: methylandrostenediol 2.1, androstanolone 13.2, 19-nortestosterone cyclopentylpropionate 16.2. 3. The myotrophic potencies, expressed as percentages of the potency of testosterone propionate, were: methylandrostenediol 2.2, androstanolone 21.8, 19-nortestosterone cyclopentylpropionate 155. 4. The myotrophic/androgenic ratios of these compounds are, therefore: methylandrostenediol 1.0, androstanolone 1.7, 19-nortestosterone cyclopentylpropinate 9.5.

Influence of nortestosterone cyclopentylpropionate on erythropoiesis in castrate male rat.

Summary 1. Long-time castrated male rats had a mean circulating red blood cell count of 8.70 ‡ .43 million cells/cu mm before treatment. Treatment with testosterone propionate (TP) or nortestosterone cyclopentylpropionate (NTCP) at daily doses of .25 mg or 1 mg for 27 days increased the number of cells to group averages of 9.52 to 10.14 mil-lion/cu mm. Blank-injected controls had RBC counts averaging 8.42 million at the end of the experimental period. 2. Hemoglobin concentration rose from a pretreatment mean of 17.88 g/100 ml to group averages of 19.1 to 20.0 g/100 ml during steroid treatment. Blank-injected controls had 17.8 g/100 ml at the end of the treatment period. 3. It is concluded that nortestosterone cyclopentylpropionate is similar to testosterone propionate in causing increases in red cell count and Hb in the castrate rat.